Metabolic manifestations of insulin deficiency do not occur without glucagon action

Young H Lee, Eric D Berglund, May-Yun Wang, Xiaorong Fu, Xinxin Yu, Maureen J. Charron, Shawn C Burgess, Roger H Unger

Research output: Contribution to journalArticlepeer-review

117 Scopus citations


To determine unambiguously if suppression of glucagon action will eliminate manifestations of diabetes, we expressed glucagon receptors in livers of glucagon receptor-null (GcgR-/-) mice before and after β-cell destruction by high-dose streptozotocin. Wild type (WT) mice developed fatal diabetic ketoacidosis after streptozotocin, whereas GcgR-/- mice with similar β-cell destruction remained clinically normal without hyperglycemia, impaired glucose tolerance, or hepatic glycogen depletion. Restoration of receptor expression using adenovirus containing the GcgR cDNA restored hepatic GcgR, phospho-cAMP response element binding protein (P-CREB), and phosphoenol pyruvate carboxykinase, markers of glucagon action, rose dramatically and severe hyperglycemia appeared. When GcgR mRNA spontaneously disappeared 7 d later, P-CREB declined and hyperglycemia disappeared. In conclusion, the metabolic manifestations of diabetes cannot occur without glucagon action and, once present, disappear promptlywhen glucagon action is abolished. Glucagon suppression should be a major therapeutic goal in diabetes.

Original languageEnglish (US)
Pages (from-to)14972-14976
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number37
StatePublished - Sep 11 2012


  • Glucagon receptor knockout
  • Glucose turnover
  • Type 1 diabetes

ASJC Scopus subject areas

  • General


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